Tumor necrosis factor alpha (TNF.alpha.) is a proinflammatory cytokine with pleiotropic effects (Tracey et al. (1989) Lancet 1:1122; Vilcek et al. (1991) J. Biol. Chem. 266:7313). During the past several years, data have accumulated that suggest that TNF.alpha. plays a role in the pathophysiology of a variety of cardiac disorders. For example, elevated circulating levels of TNF.alpha. have been reported in a variety of cardiac disorders, including acute myocarditis (Matsumori et al. (1994) Br. Heart J. 72:561), cardiac allograft rejection (Arbustini et al. (1991) Am. J. Pathol. 139:709), myocardial infarction (Latini et al. (1994) J. Cardiovasc. Pharmacol. 23:1), and congestive heart failure (Dutka et al. (1993) Br. Heart J. 70:141; Torre-Amione et al. (1996) J. Am. Coll. Cardiol. 27:1201). Additionally, administration of TNF.alpha. causes a left ventricular dysfunction in experimental animals (Murray et al (1996) Circ. Res. 78:154) as well as in human subjects (Suffredini et al. (1989) N. Eng. J. Med. 321:280; Hegewisch et al. (1990) Lancet 335:294). By contrast, neutralization of TNF.alpha. with antibodies ameliorates acute myocarditis (Smith et al. (1992) Circ. Res. 70:856; Yamada et al. (1994) Circulation 89:846) and cardiac allograft rejection (Shrenga et al. (1991) Transplant Proc 23:547; Bolling et al. (1992) Transplantation 53:283) in experimental animals.
Substantial amounts of TNF.alpha. have been detected in the heart after endotoxin administration (Kapadia et al. (1995) J. Clin. Invest. 96:1042), during allograft rejection (Arbustini et al. (1991) Am. J. Pathol. 139:709), after ischemia (Gurevitch et al. (1996) J. Am. Coll. Cardiol. 28:247), and in congestive heart failure (Torre-Amione et al. (1996) Circulation 93:704. Inflammatory cells and cardiomyocytes have been suggested as sources of TNF.alpha. production (Giroir et al. (1992) J. Clin. Invest. 90:693; Habib et al. (1996) Lancet 347:1151). However, the physiological significance of this local production of TNF.alpha. is not clear.
The foregoing studies suggest a relationship between TNF.alpha. production and cardiac dysfunction. However, the nature of this relationship has not heretofore been known. An understanding of the potential role of TNF.alpha. in cardiac dysfunction is needed in order to design effective diagnostic and therapeutic agents for cardiac disorders.
The present invention solves this need of the prior art. In accordance with the present invention it has been found that cardiac-specific overexpression of TNF.alpha. results in the development of the heart failure phenotype in a transgenic animal model. The present invention thus provides an in vivo model of cardiac dysfunction associated with TNF.alpha. overexpression.